WEEK 8 - drug redeployment and cancer

Question 1

problem with new drug discovery

Answer 1

it is slow and expensive

average 15 years and 800 million US$ to reach market

Question 2

one solution to expensive and new drug discovery

Answer 2

identify new uses of existing drugs

Many drugs coming to market now are improved version of drugs we already had

Question 3

drug redeployment:
positives

Answer 3

can save time and expense

Question 4

drug redeployment:
existing drugs have known..

Answer 4

pharmacokinetics and safety profiles

Question 5

drug redeployment:
most often approved by..

Answer 5

regulatory agencies for human use

Question 6

drug redeployment:
rapid evaluation

Answer 6

newly-identified uses can be rapidly evaluated in phase II clinical trials

Question 7

drug redeployment:
what assessments can be eliminated

Answer 7

drug developers can eliminate much of the toxicological and pharmacokinetics assessments

Question 8

drug redeployment:
acute promyelocytic leukaemia

Answer 8

all trans retinoic ATRA

approved by the shanghai municipality for the treatment of skin diseases such as psoriasis and acne

demonstrated that ATRA strongly induces terminal differentiation of HL-60 and fresh APL cells

1985 the first APL patient treated with ATRA in shanghia
- Retinoic acid alongside chemo

ATRA induces terminal differentiation of abnormal promyelocytes in vivo

Question 9

drug redeployment:
acute promyelocytic leukaemia
outcome

Answer 9

trials demonstrated that ATRA gave superior results to chemotherapy (The derivative of vitamin A outperforming chemotherapy)

ATRA/chemo in combination is superior to chemo or ATRA alone

the best outcome was observed in patients who received ATRA during both induction and maintenance chemotherapy with a 5-year disease free survival (DFS) of 74%

Question 10

drug redeployment:
acute promyelocytic leukaemia:
molecular basis

Answer 10

the molecular basis of APL was discovered after the benefits of ATRA had been discovered

In this disease get a chromosomal rearrangement

Chromosome 17 and 15 recombine in some way and create a fusion gene

Question 11

history of arsenic as a drug

Answer 11

a well known poison

one of the oldest drugs in both western medicine and traditional Chinese medicine

Hippocrates: treatment of skin ulcers
Chinese Treaty NeiJlng: treatment of malaria-associated periodic fever
18+19th C: for periodic fever, CML and other diseases

Question 12

arsenic
why was it stopped being used

Answer 12

was discarded as a treatment in the early 20thC because of its toxicity and the advent of radiatiion and cytotoxic CT
- Toxicity considered to be too unpredictable
So radiotherapy regimes were preferred over the use of arsenic

Question 13

arsenic-reborn

Answer 13

in early 1970s
group from Harbin medical uni in NE china
identified arsenic trioxide (ATO) as an active ingredient from an ancient anticancer remedy
used an arsenic compound to treat a variety of cancers

Question 14

arsenic-reborn
cancer treatment

Answer 14

in 1992
a crude solution of Arsenic trioxide (ATO) composed of 1% ATP with a trace amount of mercury chloride induced complete remisiion in 21 of 32 acute promyelocytic leukaemia patients

confirmed by further independent studies in the late 1990s

recent studies have identified that ATO as a single agent produces respectable rates of long-term remission in newly diagnosed patients

Question 15

ARTRA/ATO combination as a synergistic therapy

Answer 15

studies in a PML/RAR mouse model and in human NB4 APL cell line

mouse model indicated that ATRA/ATO combination could dramatically prolong the survival or even eradicate disease in animals

these results have encouraged clinical trials using ATRA/ATO combination to treat newly diagnosed APL
- without any concentional chemo

Question 16

Kaplan-Meier survival curves

Answer 16

shows overall survival over 5 years

Question 17

ARTRA/ATO combination as a synergistic therapy:
positives of treatment

Answer 17

With this treatment don’t get anywhere need the toxicities that you do with traditional chemotherapy

Part of the reason that survival is better
- Because you get less treatment related deaths

Question 18

clinical trials
representation of normal public?

Answer 18

THAT CLINICAL TRIALS DO NOT REPRESENT THE NORMAL PUBLIC!!
- Clinical trials always have exclusion criteria
- In cancer trials this is usually the exclusion of older patients
○ Frailer and less likely to tolerate the treatment

In real world more like 70-65% survival

Question 19

ATRA treatment leads to elimination of…

Answer 19

PML-RARa-positive cells

Question 20

ATRA treatment
why is it successful

Answer 20

Much lower residual disease with this combination than with either alone

This combination of drug is successful because if effects many pathways in leukaemia cells
- So very difficult to find a leukaemia cell that will mutate its way out of the problem
- So resistant to this treatment is much lower (than any other treatment)

Question 21

thalidomide in Myeloma:
history

Answer 21

thalidomide thought to have been developed by pharmaceutical company Grunnethal in germany

sold from 1957 to 1961 in almost 100 countries under at least 40 names

prescribes ot pregnant women to combat nausea and aid sleep

inadequate tests to asses drugs safety
- catastrophic results for children of women who had taken drug during pregnancies

approx. 10,000 children in Africa and Europe were born with severe malformities including phocomelia (short or absent long bones)

Question 22

the thalidomide tragedy

Answer 22

approx. 10,000 children in Africa and Europe were born with severe malformities including phocomelia (short or absent long bones)

Question 23

the thalidomide tragedy
in USA

Answer 23

impact was minimized

Frances Oldham Kelsey refused FDA-approval from an application to market thalidomide saying it needed more study

the applicant gave the tablets to doctors with the understanding that it was still under investigation

17 children in the US were born with the defects

Question 24

Thalidomide and leprosy

Answer 24

1964 israeli physician Jacon Sheskin sought to help a critically ill patient with erythema nodosum leprosum (ENL) a painful complication of leprosy

found a bottle of thalidomide tablets and remembered that it had been effective in helping mentally ill patients sleep

administered two tablets thalidomide:
- the patient slept for hours
- was able to get out of bed without aid upon awakening
- has resulted in the closure of many leprosy hospitals

Question 25

Thalidomide and leprosy
affects

Answer 25

• the patient slept for hours
• was able to get out of bed without aid upon awakening
• has resulted in the closure of many leprosy hospitals

used to control symptoms of leprosy

Question 26

Thalidomide and multiple myeloma

Answer 26

2006 FDA granted approval for thaludomide in combination iwth dexamethasone for the treatment of newly diagnosed MM patients
- approval came 7 years after reports of efficiency in literature

Question 27

Thalidomide and multiple myeloma
faster approval

Answer 27

7 years after evidence that thalidomide was effective against myeloma in voluntary studies
Dramatically reduced time in repurposing a drug that already existed
- Thalidomide is actually one of the safest drugs we have because the toxicity profile is very low (just cannot give to pregnant women)

Question 28

Thalidomide and multiple myeloma
Kaplan-Meier survival curves

Answer 28

Kaplan-Meier survival curves
Can see we are looking at prolonged decay
And they do not reach a plateau (because we are not curing people)
But can see that we can improve survival

Question 29

Thalidomides action is complex

Answer 29

achieves responses in 30% of patients whose disease is refactory to all other therapies

appears multiple mechanisms of action

Question 30

Thalidomide mechanisms of action

Answer 30

direct induction of G1 growth arrest or apoptosis in MM cells

inhibition of secretion of IL-6, the major MM growth and survival factor

inhibitor of VEGF-induced angiogenesis in the BM

inhibition of tumour cell proliferation and migration

stimulation of natural killer cell anti-MM immunity

Question 31

Thalidomide and multiple myeloma
negatives

Answer 31

most like had multiple activites against both MM cells and their niche in the bone marrow

side effects include: neuropathy, constipation and fatigue
but for many patients more effective than standard chemo

resistant occurs

Question 32

Thalidomide and multiple myeloma
newer medicine

Answer 32

lenalidominde and pomalidomide

2nd and 3rd gen analogues of thalidomide

Action of drug reemployments feeding in and informing drug redevelopment
Approaches working in harmony

Question 33

Thailodomide and analogues:
what unites their different mechanisms of action

Answer 33

cereblon is the target that unites all the complex activities

2010
This paper in science claimed that they had found that taregt that thalidomode attacked to created the deformities in embryos and in children of the pregnant moms take it

It was the protein cereblon
Cereblon is part of the E3 ubiquitin ligase complex
This directs ubiquitination of targets to be degraded in the proteasome

When thalidomide binds to this it changes the affinity of the complex and allows it to see substrates that it wouldn’t have normally seen
- These are called neo substrates
So has knock on effects that lead to abnormal foetal development

So does such a small dose only effect myeloma cells (without effecting the rest of the body) ??

Question 34

Drug redeployment in older patients:
AML patients

Answer 34

Age distribution
Disease of older people
Older people fair badly against this disease

Question 35

Drug redeployment in older patients:
AML patients
trial

Answer 35

medroxyprogesteron acetate (provera)
- Synthetic steroid used as a female contraceptive

Bezafibrate (Bezalip)
-Predates statins in controlling cholesterol levels

median patient age 75
13 patients has prior MDS
very poor prognosis
no improvement without effective anti-AML therapy

reasonable improvements

Question 36

Drug redeployment in older patients:
AML patients
argument for how drugs worked

Answer 36

the two drugs created reactive oxygen species

ROS causes this complex to break up
Stopping transcription factor being sent to the proteasome

Allows transcription factor to move into the nucleus and will induce these antioxidant type genes

there was evidence that valproate stopped Nrf2 going to the nucleus
and prevents transcription of these genes

Question 37

Drug redeployment in older patients:
AML patients
why didnt trial work

Answer 37

Responses not big enough for it to be seen worthwhile in practice

Question 38

failed cancer drug finding new uses:
leishmaniasis
“black fever”

Answer 38

widespread infectious disease in tropical or subtropical regions

diseased caused by a sandfly-transmitted parasite and kills an estimated 500,000 people each year

the death rate is high and alarming because of an increasing resistance against the classical therapies

Question 39

failed cancer drug finding new uses:
Miltefosine and “black fever”

Answer 39

initially developed for breast cancer

now used for treating visceral leishmaniasis

failed phase II testing fro tumour reduction and the drug was never approved by the FDA fro cancer therapy

however, in vitro and animal studies indicated anti-infective activity

phase II trials confirmed miltefosine as a viable treatment for “black fever”

cure rates of nearly 100% were observed in patient studies in india

Question 40

closing comments:
drug redeployment is a…

Answer 40

powerful approach to improving patient outcomes

Question 41

closing comments:
successful drug redeployment is…

Answer 41

targeted

Anything that works is targeted
- If it works just then need to find the target

Question 42

closing comments:
failed drugs can be…

Answer 42

powerful new resources

Question 43

closing comments:
works both the case of…

Answer 43

drug coming into cancer and failed cancer drugs finding value in other diseases

Question 44

closing comments:
drug redeployment can lead to…

Answer 44

informed development of improved second and third generation drugs